P38 MAP kinase inhibitors

ABSTRACT

There is provided inter alia a compound of formula (I): 
                         
wherein R 1 , J, Ar, L, X, R 3  and R 4  are as defined in the specification, for use in the treatment of inflammatory disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 13/639,887 filed Oct. 8, 2012, now allowed, which is a 371 ofInternational Application Number PCT/GB 2011/050697, filed Apr. 8, 2011,which claims the benefit of European Application Number 10159377.0,filed Apr. 8, 2010. The entire contents of each of the aforesaidapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates to compounds which are inhibitors of p38mitogen-activated protein kinase enzymes (referred to herein as p38 MAPkinase inhibitors), for example the alpha and gamma kinase sub-typesthereof, and their use in therapy, including in pharmaceuticalcombinations, especially in the treatment of inflammatory diseases,including inflammatory diseases of the lung, such as COPD.

BACKGROUND OF THE INVENTION

Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively) havebeen identified, each displaying a tissue-specific expression pattern.The p38 MAPK alpha and beta isoforms are ubiquitously expressedthroughout the body and are found in many different cell types. The p38MAPK alpha and beta isoforms are inhibited by certain known smallmolecule p38 MAPK inhibitors. Earlier generations of compounds werehighly toxic due to the ubiquitous expression pattern of these isoformsand off-target effects of the compounds. More recent inhibitors areimproved to be highly selective for p38 MAPK alpha and beta isoforms andhave a wider safety margin.

Less is known about the p38 MAPK gamma and delta isoforms. Theseisoforms are expressed in specific tissues/cells (unlike the p38 alphaand p38 beta isoforms). The p38 MAPK-delta isoform is expressed more inthe pancreas, testes, lung, small intestine and kidney. It is alsoabundant in macrophages (Smith, S. J. (2006) Br. J. Pharmacol,149:393-404) and detectable in neutrophils, CD4+ T cells and endothelialcells (www.genecard.org. Karin, K. (1999) J. Immunol.). Very little isknown about the expression of p38 MAPK gamma but it is expressed more inbrain, skeletal muscle and heart, as well as in lymphocytes andmacrophages (www.genecard.org).

Selective small molecule inhibitors of p38 MAPK-gamma and p38 MAPK-deltaare not currently available, but one existing compound. BIRB 796, isknown to have pan-isoform inhibitory activity. The p38 gamma and p38delta inhibition is observed at higher concentrations of the compoundthan those required to inhibit p38 alpha and p38 beta (Kuma, Y. (2005)J. Biol. Chem. 280:19472-19479). BIRB 796 also impaired thephosphorylation of p38 MAPKs or JNKs by the upstream kinase MKK6 orMKK4. Kuma discussed the possibility that the conformational changecaused by the binding of the inhibitor to the MAPK protein may affectthe structure of both its phosphorylation site and the docking site forthe upstream activator, therefore impairing the phosphorylation of p38MAPKs or JNKs.

p38 MAP kinase is believed to play a pivotal role in many of thesignalling pathways that are involved in initiating and maintainingchronic, persistent inflammation in human disease, for example, insevere asthma and COPD. There is now an abundant literature whichdemonstrates that p38 MAP kinase is activated by a range ofpro-inflammatory cytokines and that its activation results in therecruitment and release of further pro-inflammatory cytokines. Indeed,data from some clinical studies demonstrate beneficial changes indisease activity in patients during treatment with p38 MAP kinaseinhibitors. For instance Smith, S. J. (2006) Br. J, Pharmacol.149:393-404 describes the inhibitory effect of p38 MAP kinase inhibitorson TNFα (but not IL-8) release from human PBMCs. Use of inhibitors ofp38 MAP kinase in the treatment of chronic obstructive pulmonary disease(COPD) is proposed. Small molecule inhibitors targeted to p38 MAPKα/βhave proved to be effective in reducing various parameters ofinflammation in cells and tissues obtained from patients with COPD, whoare generally corticosteroid insensitive, (Smith, S. J. (2006) Br. J.Pharmacol. 149:393-404) and in vivo animal models (Underwood, D. C. etal. Am. J. Physiol. (2000) 279:L895-902; Nath, P. et al., (2006) Eur. J.Pharmacol. 544; 160-167). Irusen and colleagues also suggested thepossibility of involvement of p38 MAPKα/β on corticosteroidinsensitivity via reduction of binding affinity of glucocorticoidreceptor (GR) in nuclei (Irusen. E. et al., (2002) J. Allergy Clin.Immunol., 109:649-657). Clinical experience with a range of p38 MAPkinase inhibitors, including AMG548, BIRB 796, VX702, SCIO469 andSCIO323 is described in Lee et al. (2005) Current Med. Chem.12:2979-2994.

COPD is a condition in which the underlying inflammation is reported tobe substantially resistant to the anti-inflammatory effects of inhaledcorticosteroids. Consequently, a superior strategy for treating COPDwould be to develop an intervention which has both inherentanti-inflammatory effects and the ability to increase the sensitivity ofthe lung tissues of COPD patients to inhaled corticosteroids. The recentpublication of Mercado et al (2007; American Thoracic Society AbstractA56) demonstrates that silencing p38 gamma has the potential to restoresensitivity to corticosteroids. Thus there may be a “two pronged”benefit to the use of a p38 MAP kinase inhibitor for the treatment ofCOPD and severe asthma.

However, the major obstacle hindering the utility of p38 MAP kinaseinhibitors in the treatment of human chronic inflammatory diseases hasbeen the toxicity observed in patients. This has been sufficientlysevere to result in the withdrawal from clinical development of many ofthe compounds progressed, including all those specially mentioned above.

There remains a need to identify and develop new compoundstherapeutically useful as p38 MAP kinase inhibitors which have improvedtherapeutic potential, in particular which are more efficacious, longeracting and/or less toxic at the relevant therapeutic dose. An objectiveof the present invention is to provide compounds which inhibit p38 MAPkinase, for example with certain sub-type specificity, which show goodanti-inflammatory potential, in particular suitable for use in therapy.

SUMMARY OF THE INVENTION

According to the invention there is provided a compound of formula (I)

wherein;

-   J represents

-   Ar is a naphthylene or phenyl ring either of which may be optionally    substituted by one more groups (e.g. 1, 2 or 3 groups) independently    selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, amino. C₁₋₄ mono alkyl amino    and C₂₋₈ di-alkyl amino;-   Q is N, or CH;-   R¹ is H,    -   phenyl, or    -   a saturated or unsaturated branched or unbranched C₁₋₁₀ alkylene        in the form of an acyclic or alicyclic chain wherein one or more        carbons in the chain (for example 1 to 3, such as 1, 2 or 3        carbons) are optionally replaced by a heteroatom(s)        independently selected from —O—, —N— and S(O)_(n) and the chain        is optionally substituted by:        -   one oxo group, and/or        -   one or more halogen atoms (for example 1 to 6);-   R^(2a) is H, halo, saturated or unsaturated branched or unbranched    C₁₋₆ alkylene chain, wherein one or more carbons (for example 1 to    3, such as 1, 2 or 3 carbons) are optionally replaced by a    heteroatom(s) independently selected from —O—, —N— and/or S(O)_(m)    and the chain is optionally substituted by one or more halogen atoms    (for example 1 to 6);-   R^(2b) is H, halo, C₁₋₆ alkoxy or C₁₋₆ alkyl optionally substituted    by OH:-   L is saturated or unsaturated branched or unbranched C₁₋₆ alkylene    chain (such as a C₁₋₃ alkylene), wherein one or more carbons (for    example 1 to 3, such as 1, 2 or 3 carbons) are optionally replaced    by a heteroatom selected from —O— and/or S. and the chain is    optionally substituted by one or two oxo groups (for example 1 or    2);-   X is a pyridine or pyrimidine ring optionally substituted by C₁₋₃    alkyl, or C₁₋₃ haloalkyl;-   R³ H or C₁₋₄ alkyl;-   R⁴ is C₁₋₁₀ branched or unbranched acyclic or alicyclic alkyl chain-   n is 0, or 2;-   m is 0, 1 or 2;    or    a pharmaceutically acceptable salt thereof, including all    stereoisomers, tautomers and isotopic derivatives thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention are kinase inhibitors, possessing, forexample, potent inhibitory activity at p38 MAPK enzymes and may, showselectivity for the p38-alpha isoform over the p38-gamma isoform. Thecompounds display efficacy in established in vitro assays ofanti-inflammatory activity. For example compounds of the inventiondemonstrate the ability to block LPS-induced TNFα release fromdifferentiated U937 cells and THP-1 cells and similarly to block thestimulated release of IL-8 from differentiated U937 cells.

According to the invention the compounds provided herein are especiallysuitable for treating inflammatory pulmonary diseases by topicaladministration since they are believed to have properties that result inlong residency times in the lung, resulting in an extended duration oftherapeutic action, which is consistent with twice or even once, dailydosing.

In addition it is believed that one or more compounds of the inventionmay also possess certain antiviral activities making them useful forpreventing or ameliorating the symptoms of viral infection in patients,for example with inflammatory lung disorders.

The properties, described above (alone or in combination), distinguishthe compounds according to the invention from other known compounds,which do not possess these desirable so features.

Alkyl as used herein refers to straight chain or branched chain alkyl,such as, without limitation, methyl, ethyl, n-propyl, iso-propyl, butyl,n-butyl and tert-butyl. In one embodiment alkyl refers to straight chainalkyl.

Alkoxy as used herein refers to straight or branched chain alkoxy, forexample methoxy, ethoxy, propoxy, butoxy. Alkoxy as employed herein alsoextends to embodiments in which the oxygen atom is located within thealkyl chain, for example —C₁₋₃ alkylOC₁₋₃ alkyl, such as —CH₂CH₂OCH₃ or—CH₂OCH₃. Thus in one embodiment the alkoxy is linked through carbon tothe remainder of the molecule. In one embodiment the alkoxy is linkedthrough oxygen to the remainder of the molecule, for example —OC₁₋₆alkyl. In one embodiment the disclosure relates to a straight chainalkoxy.

Heteroalkyl as employed herein is intended to refer to a branched orstraight chain alkyl wherein one or more, such as 1, 2 or 3 carbons arereplaced by a heteroatom, selected from N, O or S(O)_(r), wherein rrepresents 0, 1 or 2. The heteroatom may replace a primary, secondary ortertiary carbon, that is, for example, SH, OH or NH₂ for CH₃, or NH or Oor SO₂ for —CH₂— or N for a —CH— or a branched tertiary carbon, astechnically appropriate.

Haloalkyl as employed herein refers to alkyl groups having 1 to 6halogen atoms, for example 1 to 5 halogens, including perhaloalkyl, inparticular perchloroalkyl or perfluoroalkyl, more specifically —CCl₃,—CF₂CF₃ or CF₃.

C₁₋₄ mono acyl amino and C₂₋₈ di-acyl amino are intended to refer to—NHC(O)C₁₋₄ alkyl and to —N(C═OC₁₋₄alkyl) (C═OC₁₋₄ alkyl) respectively.

C₁₋₄ mono alkyl amino and C₂₋₈ di-alkyl amino are intended to refer to—NHC₁₋₄ alkyl and to —N(C₁₋₄ alkyl) (C₁₋₄ alkyl) respectively.

Aryl as used herein refers to, for example C₆₋₁₄ mono or polycyclicsystems having from 1 to 3 rings wherein at least one ring is aromaticincluding phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthyl andthe like, such as phenyl and naphthyl.

Heteroaryl is a 6 to 10 membered aromatic monocylic ring or bicyclicring system wherein at least one ring is an aromatic nucleus comprisingone or more, for example 1, 2, 3 or 4 heteroatoms independently selectedfrom O, N and S. Examples of heteroaryls include: pyrrole, oxazole,thiazole, isothiazole, imidazole, pyrazole, isoxazole, pyridine,pyridazine, pyrimidine, pyrazine, benzothiophene, benzofuran, or 1, 2, 3and 1, 2, 4 triazole.

Heterocyclyl as employed herein refers to a 5 to 6 membered saturated orpartially unsaturated non-aromatic ring comprising one or more, forexample 1, 2, 3 or 4 heteroatoms independently selected from O, N and Soptionally one or two carbons in the ring may bear an oxo substituent.The definition of C₅₋₆ heterocycle as employed herein refers to a 5 to 6membered saturated or partially unsaturated non-aromatic carbocyclicring comprising one or more, for example 1, 2, 3 or 4 heteroatomsindependently selected from O, N and S, wherein each heteroatom replacesa carbon atom and optionally one or two carbons may bear an oxosubstitutent. Clearly any valancies of a heteroatom not employed informing or retaining the ring structure may be filled by hydrogen or asubstituent, as appropriate. Thus substituents on heterocycles may be oncarbon or on a heteroatom, such as nitrogen as appropriate. Examples ofheterocycles and C₅₋₆ heterocycles include pyrroline, pyrrolidine,tetrahydrofuran, tetrahydrothiophene, pyrazoline, imidazoline,pyrazolidine, imidazolidine, oxoimidazolidine, dioxolane, thiazolidine,isoxazolidine, pyran, dihydropyran, piperidine, piperazine, morpholine,dioxane, thiomorpholine and oxathiane.

Halogen includes fluoro, chloro, bromo or iodo, in particular fluoro,chloro or bromo, especially fluoro or chloro.

Oxo as used herein refers to C═O and will usually be represented asC(O).

C₃₋₈ cycloalkyl as employed herein is intended to refer to a saturatedor partially unsaturated non-aromatic ring containing 3 to 8 carbonatoms, where the ring contains less than 8 carbons the ring mayoptionally bear one or more alkyl groups such that the number of carbonatoms in the ring plus the number of carbons in the alkyl substituentsis not more than eight in total or 10 in the case of C₃₋₁₀ cycloalkyls.

C₁₋₁₀ alkyl includes C₂, C₃, C₄, C₅, C₆, C₇, C₈ or C₉ as well as C₁ andC₁₀.

C₀₋₈ alkyl includes C₁, C₂, C₃, C₄, C₅, C₆, or C₇ as well as C₀ and C₈.

In relation to a saturated or unsaturated, branched or unbranched C₁₋₁₀alkyl chain (or similar language used herein), wherein at least onecarbon (for example 1, 2 or 3 carbons, suitably 1 or 2, in particular 1)is replaced by a heteroatom selected from O, N, S(O)_(p), wherein saidchain is optionally, substituted by one or more groups independentlyselected from oxo and halogen, it will be clear to persons skilled inthe art that the heteroatom may replace a primary, secondary or tertiarycarbon, that is CH₃, —CH₂— or a —CH—, a tertiary carbon group or —CH═,as technically appropriate.

Saturated or unsaturated, branched or unbranched C₁₋₁₀ alkyl alicyclicchain is intended to refer to C₃₋₁₀ cycloalkyl.

In one embodiment J represents:

In one embodiment J represents:

In one embodiment R¹ is —C₁₋₆ alkyl optionally substituted by OH, C₃₋₁₀cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylOC(O)CH₃.

In one embodiment of the disclosure there is provided compounds offormula (I), wherein R¹ is methyl, ethyl, propyl, iso-propyl, butyl ortert-butyl, in particular tert-butyl.

In one embodiment R¹ is —C(CH₃)₂CH₂OH.

In one embodiment R¹ is cyclopropyl, or 1-methylcyclopropyl,cyclopentyl, cyclohexyl, or 1-methylcyclohexyl, or adamantly.

In one embodiment R¹ is tetrahydropyranyl or4-methyltetrahydro-2H-pyran-4-yl.

In one embodiment R¹ is —CF₃, —CF₂CF₃ or —CCl₃.

In one embodiment R¹ is phenyl.

In one embodiment the substituent R^(2a) is in the 2, 3, or 4 position(i.e. ortho, meta or para position), in particular the para (4-)position relative to the attachment of the aromatic ring J to thepyrazole system.

In one embodiment R^(2a) is methyl, ethyl, n-propyl, iso-propyl, n-butylor tert-butyl, in particular methyl, for example in position 3 or 4.

In one embodiment R^(2a) is —OH, for example in position 3 or 4.

In one embodiment R^(2a) is halo such as chloro, for example in position3 or 4.

In one embodiment R^(2a) is —C₁₋₆ alkyl substituted by a hydroxyl groupsuch as —CH₂OH, for example in position 3 or 4.

In one embodiment R^(2a) is —C₁₋₆ alkoxy, such as —OCH₃, for example inposition 3 or 4.

In one embodiment R^(2a) is —SC₁₋₆ alkyl, such as —SCH₃, for example inposition 3 or 4.

In one embodiment R^(2a) is —SO₂C₁₋₆ alkyl, such as —SO₂CH₃ for examplein the 3 or 4 position.

In one embodiment R^(2a) is —OCF₃, for example located in position 3 or4.

In one embodiment R^(2a) is —NR′R″ wherein R′ is H, —C₁₋₃ alkyl or—SO₂C₁₋₃alkyl, and R″ is H or —C₁₋₃ alkyl, for example located inposition 3 or 4. In one embodiment R^(2a) is —NH₂, for example inposition 3 or 4.

In one embodiment R^(2a) is —NHSO₂CH₃, for example in position 3 or 4.

In one embodiment R^(2b) is H.

In one embodiment R^(2b) is halo such as chloro, for example in position3.

In one embodiment R^(2a) is chloro and R^(2b) is chloro, for example3,4-dichloro.

In one embodiment R^(2a) chloro is and R^(2b) is —OCH₃, for example inpositions 3,4 respectively.

In one embodiment R^(2a) is —OCH₃ and R^(2b) is —OCH₃, for example inposition 3,4.

In one embodiment R^(2a) chloro is and R^(2b) is —OH, for example inposition 3,4 respectively.

In one embodiment the substituent R^(2a) is in the 2, 3, or 4 position(i.e. ortho, meta or para position), in particular the para (4-)position relative to the attachment of the aromatic ring J to thepyrazole system.

In one embodiment R^(2a) is methyl, ethyl, n-propyl, iso-propyl, n-butylor tert-butyl, in particular methyl, for example in position 3 or 4.

In one embodiment R^(2a) is —OH, for example in position 3 or 4.

In one embodiment R^(2a) is halo such as chloro, for example in position3 or 4.

In one embodiment R^(2a) is —C₁₋₆ alkyl substituted by a hydroxyl groupsuch as —CH₂OH, for example in position 3 or 4.

In one embodiment R^(2a) is —C₁₋₆ alkoxy, such as —OCH₃, for example inposition 3 or 4.

In one embodiment R^(2a) is —SC₁₋₆ alkyl, such as —SCH₃, for example inposition 3 or 4.

In one embodiment R^(2a) is —SO₂C₁₋₆ alkyl, such as —SO₂CH₃ for examplein the 3 or 4 position.

In one embodiment R^(2a) is —OCF₃, for example located in position 3 or4.

In one embodiment R^(2a) is —NR′R″ wherein R′ is H, —C₁₋₃ alkyl or—SO₂C₁₋₃alkyl, and R″ is H or —C₁₋₃ alkyl, for example located inposition 3 or 4. In one embodiment R^(2a) is —NH₂, for example inposition 3 or 4.

In one embodiment R^(2a) is —NHSO₂CH₃, for example in position 3 or 4.

In one embodiment R^(2b) is H.

In one embodiment R^(2b) is halo such as chloro, for example in position3.

In one embodiment R^(2a) is chloro and R^(2b) is chloro, for example3,4-dichloro.

In one embodiment R^(2a) chloro is and R^(2b) is —OCH₃, for example inpositions 3,4 respectively.

In one embodiment R^(2a) is —OCH₃ and R^(2b) is —OCH₃, for example inposition 3,4.

In one embodiment R^(2a) chloro is and R^(2b) is —OH, for example inposition 3,4 respectively.

In embodiments of the invention wherein the group Q represents N, thesubstituents R^(2a) and R^(2b) on the ring are pharmaceuticallyacceptable and do not include those of a highly reactive nature (such asa halogen atom disposed ortho to the heteroatom) such that compounds offormula (I) would thereby be rendered unstable and consequentlyunsuitable for their intended utility.

In one embodiment J is pyridine and R^(2a) is methyl, ethyl, n-propyl,iso-propyl, n-butyl or tert-butyl, in particular methyl, for example inposition 2 or 3.

In one embodiment J is pyridine and R²¹ is —C₁₋₆ alkyl substituted by ahydroxyl group such as —CH₂OH, for example in position 2 or 3.

In one embodiment J is pyridine and R^(2a) is —C₁₋₆ alkoxy, such as—OCH₃, for example in position 2 or 3.

In one embodiment J is pyridine and R^(2a) is —SC₁₋₆ alkyl, such as—SCH₃, for example in position 2 or 3.

In one embodiment J is pyridine and R^(2a) is —SO₂C₁₋₆ alkyl, such as—SO₂CH₃ for example in the 3 position.

In one embodiment J is pyridine and R^(2a) is —OCF₃, for example locatedin position 3.

In one embodiment when J is pyridine and R^(2a) is —NR′R″ wherein R′ isH, —C₁₋₃ alkyl or —SO₂C₁₋₃alkyl, and R″ is H or —C₁₋₃ alkyl, for examplelocated in position 2 or 3. In one embodiment R^(2a) is —NH₂, forexample in position 2 or 3.

In one embodiment J is pyridine and R^(2a) is —NHSO₂CH₃, for example inposition 2 or 3.

In one embodiment J is pyridine and R^(2b) is H.

In one embodiment L represents O, CH₂, C═O or S(O)_(t) where t is 0, 1or 2, in particular 0 or 2.

In one embodiment L represents —OCH₂— or —OCH₂CH₂—.

In one embodiment X is pyridine.

In one embodiment R³ is H.

In one embodiment R⁴ is an unbranched alkyl, for example methyl, ethyl,propyl, butyl, pentyl, hexyl, nonyl, decyl, such as methyl.

In one embodiment R⁴ is a branched alkyl, for example —CH₂CH(CH₃)₂,—C(CH₃)₃, CH₂CH(CH₃)CH₂CH₃ and the like.

In one embodiment the disclosure relates to compounds of formula (IA):

wherein Ar, R¹, R^(2a), R^(2b), R³, R⁴, L and X, are as defined abovefor compounds of formula (I).

In one embodiment the disclosure relates to compounds of formula (IB):

wherein Ar, R¹, R^(2a), R³, R⁴, L and X are as defined above forcompounds of formula (I).

In one embodiment the disclosure relates to compounds of formula (IC):

wherein R¹, R^(2a), R^(2b), R³, R⁴, L and X are as defined above forcompounds of formula (I).

In one embodiment the disclosure relates to compounds of formula (ID):

wherein R¹, R^(2a), R³, R⁴, L and X are as defined above for compoundsof formula (I).

In one embodiment the disclosure relates to compounds of formula (IE):

wherein R¹, R^(2a), R^(2b), R³, R⁴ and L are as defined above forcompounds of formula (I).

In one embodiment of the invention the compounds of formula (IE)comprise of structures in which the substituent —NR³C(O)R⁴ is located atposition 2 of the pyridine ring.

In one embodiment the disclosure relates to compounds of formula (IF):

wherein R¹, R^(2a), R³, R⁴ and L are as defined above for compounds offormula (I).

In one embodiment of the invention the compounds of formula (IF)comprise of structures in which the substituent —NR³C(O)R⁴ is located atposition 2 of the pyridine ring.

In one embodiment the compound is:

-   N-(4-(2-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide;-   N-(4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)acetamide:-   N-(4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)acetamide;    or a pharmaceutically acceptable salt of any one thereof, including    all stereoisomers, tautomers and isotopic derivatives thereof.

Examples of salts of compound (I) include all pharmaceuticallyacceptable salts, such as, without limitation, acid addition salts ofmineral acids such as HCl and HBr salts and addition salts of organicacids such as a methanesulfonic acid salt. Further example salts includepharmaceutically acceptable acid addition salts which can convenientlybe obtained by treating the base form with an appropriate acid, forexample, inorganic acids such as sulfuric, nitric and phosphoric acids:or organic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic or pamoic acids.

The disclosure herein extends to solvates of compounds of formula (I).Examples of solvates include hydrates.

The compounds of the disclosure include those where the atom specifiedis a naturally occurring or non-naturally occurring isotope. In oneembodiment the isotope is a stable isotope. Thus the compounds of thedisclosure include, for example, deuterium containing compounds and thelike.

The compounds described herein may include one or more stereogeniccentres, and the disclosure extends to include racemates, and to bothenantiomers (for example each substantially free of the otherenantiomer) and all stereoisomers, such as diastereomers resultingtherefrom. In one embodiment one enantiomeric form is present in apurified form that is substantially free of the correspondingentaniomeric form.

The disclosure also extends to all polymorphic forms of the compoundsherein defined.

Compounds of formula (I) can be prepared by a process comprisingreacting a compound of formula (II):

wherein J, L X, R¹, R³ and Q are as defined above for compounds offormula (I) with a compound of formula (III):

Where R⁴ is as defined above and LG₁ is a leaving group for examplehalogen, such as chloro. The reaction is suitably carried out in thepresence of an organic base such as DIPEA or triethylamine and in anaprotic solvent or solvent mixture such as a mixture of DCM and DMF.

Alternatively compounds of formula (I) can be prepared by reacting acompound of formula (V):

where R¹ and J are as defined above for compounds of formula (I), with acompound of formula (IV):

wherein LG₃ and LG₄ each independently represent leaving groups, togenerate a compound of formula (VIa), for example when LG₃ and LG₄ bothrepresent imidazolyl; or a compound of formula (VIb), for example whenthe groups LG₃ and LG₄ represent halogen, such chloro or trihalomethoxysuch as trichloromethoxy)

followed by reaction with a compound of formula (VII):

wherein R³, R⁴, L, X, and Ar are as defined above for compounds offormula (I). The reaction is suitably carried out in an aprotic solventsuch as dichloromethane in the presence of a sterically hindered base,for example DIPEA.

It will be understood by persons skilled in the art that compoundsrepresented by formulae (VIa) and (VIb) are generally reactiveintermediates, and may be formed in situ and reacted directly, withoutisolation, with a compound of formula (VII) to provide a compound offormula (I). Furthermore it will be understood by those skilled in theart that the use of appropriate protective groups may be required duringthe processes described above, for any of the groups R¹, R^(2a) andR^(2b) on J that comprise chemically sensitive functional groups, forexample that contain a OH group or an NH₂ function

Compounds of formula (II) can be prepared by reacting a compound offormula (VIII) wherein R³, Ar, L and X are as defined above forcompounds of formula (I)H₂N—Ar-L-X—NHR³  (VIII)with a compound of formula (VIa) or a compound of formula (VIb),generated as described above from a compound of formula (V), in anaprotic solvent such as dichloromethane and a suitable base, for exampleDIPEA, employing, where necessary, appropriate protective groups forchemically sensitive functionality.

Compounds of formula (VII) may be prepared by reacting a compound offormula (IX):O₂N—Ar-L-X—NHR³  (IX)wherein R³, Ar, L and X are as defined above for compounds of formula(I), with a compound of formula (III). The reaction is suitably carriedout in the presence of an organic base such as DIPEA or triethylamine inan aprotic solvent or solvent mixture, such as DCM and DMF.

From the intermediate so generated compounds of formula (VII) are thenrevealed by reduction of the nitro arene to the corresponding amine, forexample by hydrogenation in the presence of a suitable catalyst, such aspalladium on carbon. In certain cases it may be advantageous to conductthe reduction step chemically, for example under dissolving metalconditions, such as with iron in glacial acetic acid.

Compounds of formula (V) can be derived from the condensation of aphenylhydrazine of formula (X) or (Xa):

wherein J, R^(2a), R^(2b) and Q are as are defined above for compoundsof formula (I), with a compound of formula (XI):

wherein R¹ is as defined above for compounds of formula (I).

The reaction may be effected in an alcoholic solvent such as ethanol andin the presence of a mineral acid, such as HCl followed by treatmentwith a base, such as lithium hydroxide, in a solvent such as THF, toliberate the product as a free base.

Compounds of formula (I) wherein any of the substituents R¹ or R^(2a) orR^(2b) contains a sensitive functional group may be prepared from acompound of formula (V), by the processes described above, in which thesaid functionality is suitably protected during the synthetictransformations, followed by an appropriate deprotection step. Forexample a compound of formula (V) in which R¹, or R^(2a) or R^(2b)comprises a hydroxyalkyl, may be converted into a compound of formula(I) by the methods described above, by protecting the hydroxylfunctionality, for example as a silyl ether. The hydroxyl group can berevealed at the end of the synthetic sequence by cleavage of theprotective group: for example a silyl protective group may be removedwith, for example, tetrabutylammonium fluoride.

Compounds of formula (V) wherein any of the substituents R¹, or R^(2a)or R^(2b) consists of a hydroxyalkyl such as, for example,—(CH₂)_(x)CH₂OH may be prepared by the reduction of compounds of formula(V) in which one or more of the substituents R¹, or R^(2a) or R^(2b)comprises of the corresponding acid such as, for example —(CH₂)_(x)CO₂H,wherein x is as appropriate for compounds of formula (I), employing areagent such as borane in a suitable solvent, for example THF. Thehydroxyl may then be optionally protected, for example as a silyl ether,and this intermediate converted into a compound of formula (I) in whichR¹, or R^(2a) or R^(2b) is a protected hydroxyalkyl group, by one of themethods described above.

Compounds of formula (VIII) may be prepared by the reduction of acompound of formula (IX) to the corresponding amine, for example usinghydrogenation in the presence of a suitable catalyst such as palladiumon carbon.

Certain compounds of formula (IX) wherein the group L comprises of afragment represented by —O(CH₂)₁₋₅— may be obtained by the reaction of acompound of formula (XIIa), wherein X and R³ are as defined forcompounds of formula (I)HO—(CH₂)₁₋₅—X—NHR³  (XIIa)and a compound of formula (XIII):O₂N—Ar—OH  (XIII)wherein Ar is as defined above for compounds of formula (I), for exampleunder Mitsunobu coupling conditions, typically in the presence of atriarylphosphine such as triphenylphosphine and a dialkylazodicarboxylate such as diisopropylazodicarboxylate. The reaction issuitably carried out in a polar aprotic solvent such as THF.

Alternatively, certain compounds of formula (IX) wherein the group Lcomprises of a fragment represented by —O(CH₂)₁₋₅— may be obtained by anucleophilic aromatic substitution (S_(N)Ar) reaction of a compound offormula (XIIa) with a compound of (XIV)O₂N—Ar—Z  (XIV)wherein Ar is as defined above for compounds of formula (I) and Z is ahalogen atom, most preferably fluorine. The reaction is convenientlyconducted in the presence of a strong base such as sodium hydride and inan aprotic solvent such as THF.

Certain compounds of formula (IX) wherein the group L is O, that is anoxa linker, may be obtained by the reaction of a compound of formula(XIIb), wherein X and R³ are as defined for compounds of formula (I)HO—X—NHR³  (XIIb)and a compound of formula (XIV). The reaction may be conducted in thepresence of an organic base such DBU in a polar aprotic solvent such asacetonitrile.

Certain compounds of formula (IX) wherein the group L is O, that is anoxa linker, may be obtained by the reaction of a compound of formula(XIIc), wherein X and R³ are as defined for compounds of formula (I) andY is a halogen atom preferably chlorineY—X—NHR³  (XIIc)and a compound of formula (XIII). The reaction may be effected in apolar aprotic solvent, such as NMP, in the presence of a strong mineralacid, such conc. hydrochloric acid and at an elevated temperature forexample at 170° C. to 190° C.

Certain compounds of formula (VII) wherein the group L is O, that is anoxa linker, may be obtained via the reaction of a compound of formula(XIId),

wherein X, R³ and R⁴ are as defined for compounds of formula (I) with acompound of formula (XIV) providing compounds of formula (XV).

Compounds of formula (VII) are revealed from compounds of formula (XV)by the reduction of the nitroarene to the corresponding amine. Thistransformation may be conducted by catalytic hydrogenation in a suitablesolvent mixture such as a mixture of DCM, MeOH and acetic acid, over anappropriate metal catalyst, for example platinum supported on graphite,at RT. Alternatively it may be advantageous to conduct the reductionstep by chemical means, for example using a metal such as iron powder,in an acid, such as glacial acetic acid at an elevated temperature, suchas 60° C.

Certain compounds of formula (I) wherein Ar, X, R¹, and R³ are aspreviously defined above and the group L is S, that is a thio etherlinker; may be prepared from a compound of formula (IIb), by theprocesses described above for a compound of formula (II) A compound offormula (IIb) may be obtained from a compound of (VIII) wherein Ar, R³and X are as defined above and L is S; by reaction with a compound offormula (VIa) or a compound of formula (VIb) as described above.

Compounds of formula (VIII) wherein R³, Ar, J and X are as defined aboveand L is S, that is L is a thioether linker, may be prepared from acompound of formula (VIIIc) wherein the group Ar¹ is a leaving groupwith an electron rich aromatic nucleus, thereby making the radical—CH₂Ar¹ susceptible to cleavage by acidolysis. A suitable aromatic groupfor this purpose is, for example 2,4-dimethoxybenzene and the like. Thedesired compound of formula (VIII), as defined above, may be obtainedfrom the compound of formula (VIIIc) by acid mediated cleavage, forexample with hydrochloric acid in an alcoholic solvent such methanol, atan elevated temperature such as at reflux:

Compounds of formula (VIIIc) are obtainable from the reaction of acompound of formula (XVI) wherein Ar and X are as defined above and Y isa halogen atom, preferably chlorine, with a compound of formula (XVII),wherein R³ and Ar¹ are as defined above. The reaction may be carried outby heating the compound of formula (XVII) as a solution in the neatamine of formula (XVII) at a suitable temperature, such as 120° C.:

wherein X, Y, Ar¹ and R³ are defined above.

Compounds of formula (XVI) may be prepared by reduction of compounds offormula (XVIII), for example by catalytic reduction using hydrogen and asuitable metal catalyst. The reduction step is conveniently carried outin a mixture of solvents such as EtOAc, MeOH and AcOH, over platinum oncarbon, at an elevated temperature such as 50° C.O₂N—Ar—S—X—Y  (XVIII)

Compounds of formula (XVIII) may be prepared by the reaction ofcompounds of formula (XIV), as defined above, with a compound of formula(XIX)Z—X—Y  (XIX)

wherein X is as defined above, Z is a halogen atom, preferably fluorineand Y is a halogen atom, preferably chlorine together with a suitablesulfur nucleophile. For example the reaction can be carried using sodiumhydrogensulfide as the sulfur source in a polar aprotic solvent such asDMF and in the presence of a organic base, for example DIPEA, at ambienttemperature.

Certain compounds of formula (I) wherein, R¹, R^(2a), R^(2b), Ar and Xare as previously defined, R³ is H and L is SO₂, that is L is a sulfonyllinker, may be prepared from a compound of formula (IIc) by one or moreof the processes described above.

Compounds of formula (IIc) can be derived from a compound of formula(XX),H₂N—Ar—SO₂—X—NHP¹  (XX)OCN—Ar—SO₂—X—NHP¹  (XXI)wherein Ar, X and P¹ are as previously defined, by conversion, in situ,into an isocyanate of formula (XXI) followed by, without isolation,reaction with a compound of formula (V). The transformation may beeffected by exposing the compound of formula (XX) to a compound offormula (IVb); wherein, for example, the group LG₃ is halogen such aschlorine and the group LG₄ is trihalomethoxy such as trichloromethoxy,such that the compound of formula (IVb) is diphosgene, and subsequentlyof admixing the compound of formula (V). The reaction is convenientlyconducted in an inert aprotic solvent such as DCM and may be cooled, forexample to 0° C. The desired compounds of formula (IIc) are thenrevealed from the products so obtained by a deprotection step. Forexample, where P¹ represents a Boc group the compounds of formula (IIc)are obtained following removal of the protective group with an acid suchas TFA, in an inert solvent such as DCM, conveniently at 0° C. to RT.

Compounds of formula (XX), wherein Ar, X and P¹ are as previouslydefined, may be obtained by the reduction of compounds of formula(XXII).O₂N—Ar—SO₂—X—NHP¹   (XXII)The reduction may be carried out, for example, by hydrogenation over asuitable catalyst, such as palladium on carbon, in an appropriatesolvent system such as a mixture of EtOAc, MeOH and AcOH, and ifnecessary with warming, for example at 30° C.

Compounds of formula (XXII) are accessible from compounds of formula(XVIIa)

wherein Ar and X are as previously defined above and Y is a halogenatom, preferably chlorine, by an amidation reaction employing a compoundof formula (XXIII). A suitable compound of formula (XXIII) for thistransformation is that in which R represents tert-butyl such that thesaid compound (XXIII) is H₂NC(O)O^(t)Bu. Suitable conditions for thisconversion are, for example, the reaction of a compound of formula(XVIIIa) with a compound of formula (XXV) in the presence of a catalyticsystem, such as that generated from Pd₂(dba)₃ in the presence of thephosphine ligand such as XantPhos. The reaction is convenientlyconducted in a polar aprotic solvent such as THF and in the presence ofa base, for example, an inorganic base such as cesium carbonate.

Compounds of formula (XVIIIa) wherein Ar is as previously defined and Xis pyridine may be derived from a compound of formula (XXIV):

by oxidation to a compound of formula (XXV) followed by treatment with achlorinating agent. A suitable oxidising reagent for the conversion of acompound of formula (XXIV) into a compound of formula (XXV) is, forexample, m-CPBA. The reaction may be effected in a halogenated solventsuch as DCM and typically below RT, for example at 0° C. The subsequentchlorination step may be carried out using a reagent such as phosphorusoxychloride at an elevated temperature, for example at 100° C.

Compounds of formula (XXIV) may be obtained from the reaction of acompound of formula (XIV) as defined previously, with a compound offormula (XXVI):

The reaction is conveniently conducted in a polar aprotic solvent suchas DMF and typically in the presence of a base, for example an inorganicbase such as potassium carbonate, and if necessary with cooling, forexample, to 0° C.

Compounds of formulae (III), (IVa), (IVb), (V), (X), (XI), (XIIa),(XIIb), (XIIc), (XIII), (XIV), (XVII), (XIX), (XXIII), (XXVI) andcertain other compounds illustrated in the schemes are eithercommercially available, or were obtained using the cited procedures, orcan be readily prepared by conventional methods by those skilled in theart. See for example Regan, J. et al.: J. Med. Chem., 2003, 46,4676-4686, WO00/043384, WO2007/087448 and WO2007/089512.

Protecting groups may be required to protect chemically sensitive groupsduring one or more of the reactions described above, to ensure that theprocess is efficient. Thus if desired or necessary, intermediatecompounds may be protected by the use of conventional protecting groups.Protecting groups and means for their removal are described in“Protective Groups in Organic Synthesis”, by Theodora W. Greene andPeter G. M. Wuts, published by John Wiley & Sons Inc; 4^(th) Rev Ed.,2006, ISBN-10: 0471697540.

Novel intermediates are claimed as an aspect of the invention.

In one aspect the compounds are useful in treatment, for example COPDand/or asthma.

The p38MAPK inhibitory compounds developed to date have typically beenintended for oral administration. This method of dosing involvesoptimization to achieve an adequate duration of action by selectingcompounds that have an appropriate pharmacokinetic profile. Thisstrategy ensures that a therapeutically effective drug concentration isestablished and maintained after and between doses to provide thedesired clinical benefit. The inevitable consequence of this regimen isthat all body tissues, especially liver and gut, are likely to beexposed chronically to therapeutically active concentrations of thedrug, whether or not they are adversely affected in the diseased state.

An alternative strategy is to design treatment approaches in which thedrug is dosed directly to the inflamed organ (topical therapy). Whilethis approach is not suitable for treating all chronic inflammatorydiseases, it has been extensively exploited in lung diseases (asthma,COPD), skin diseases (atopic dermatitis and psoriasis), nasal diseases(allergic rhinitis) and gastrointestinal diseases (ulcerative colitis).

In topical therapy, efficacy can be achieved either by ensuring that thedrug has a sustained duration of action and is retained in the relevantorgan to minimize the risk of systemic toxicity; or by producing aformulation which generates a “reservoir” of the active drug which isavailable to sustain the drug's desired effects. The first approach isexemplified by the anticholinergic drug tiotropium (Spiriva). Thiscompound is administered topically to the lung as a treatment for COPD,and has an exceptionally high affinity for its target receptor resultingin a very slow off rate and a consequent sustained duration of action.

There is provided according to one aspect of the present disclosure useof a compound of formulation as a p38 MAP kinase inhibitor, for exampleadministered topically to the lung.

In one aspect of the disclosure the compounds herein are particularlysuitable for topical delivery, such as topical delivery to the lungs, inparticular for the treatment of COPD.

Thus is one aspect there is provided use of compounds of formula (I) forthe treatment of COPD and/or asthma, in particular COPD or severeasthma, by inhalation i.e. topical administration to the lung.Advantageously, administration to the lung allows the beneficial effectsof the compounds to be realised whilst minimising the side-effects forpatients.

In one aspect the compounds have a longer duration of actions than BIRB796.

In one embodiment the compounds are suitable for sensitizing patients totreatment with a corticosteroid.

The compounds herein may also be useful for the treatment of rheumatoidarthritis.

Further, the present invention provides a pharmaceutical compositioncomprising a compound according to the disclosure optionally incombination with one or more pharmaceutically acceptable diluents orcarriers.

Diluents and carriers may include those suitable for parenteral, oral,topical, mucosal and rectal administration.

As mentioned above, such compositions may be prepared e.g. forparenteral, subcutaneous, intramuscular, intravenous, intra-articular orperi-articular administration, particularly in the form of liquidsolutions or suspensions; for oral administration, particularly in theform of tablets or capsules; for topical e.g. pulmonary or intranasaladministration, particularly in the form of powders, nasal drops oraerosols and transdermal administration; for mucosal administration e.g.to buccal, sublingual or vaginal mucosa, and for rectal administratione.g. in the form of a suppository.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well-known in thepharmaceutical art, for example as described in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,(1985), Formulations for parenteral administration may contain asexcipients sterile water or saline, alkylene glycols such as propyleneglycol, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, hydrogenated naphthalenes and the like.

Formulations for nasal administration may be solid and may containexcipients, for example, lactose or dextran, or may be aqueous or oilysolutions for use in the form of nasal drops or metered spray. Forbuccal administration typical excipients include sugars, calciumstearate, magnesium stearate, pregelatinated starch, and the like.

Compositions suitable for oral administration may comprise one or morephysiologically compatible carriers and/or excipients and may be insolid or liquid form. Tablets and capsules may be prepared with bindingagents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, orpoly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch,calcium phosphate, sorbitol, or glycine; lubricants, such as magnesiumstearate, talc, polyethylene glycol, or silica; and surfactants, such assodium lauryl sulfate. Liquid compositions may contain conventionaladditives such as suspending agents, for example sorbitol syrup, methylcellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or ediblefats; emulsifying agents such as lecithin, or acacia; vegetable oilssuch as almond oil, coconut oil, cod liver oil, or peanut oil;preservatives such as butylated hydroxyanisole (BHA) and butylatedhydroxytoluene (BHT). Liquid compositions may be encapsulated in, forexample, gelatin to provide a unit dosage form.

Solid oral dosage forms include tablets, two-piece hard shell capsulesand soft elastic gelatin (SEG) capsules.

A dry shell formulation typically comprises of about 40% to 60%concentration of gelatin, about a 20% to 30% concentration ofplasticizer (such as glycerin, sorbitol or propylene glycol) and about a30% to 40% concentration of water. Other materials such aspreservatives, dyes, opacifiers and flavours also may be present. Theliquid fill material comprises a solid drug that has been dissolved,solubilized or dispersed (with suspending agents such as beeswax,hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug invehicles or combinations of vehicles such as mineral oil, vegetableoils, triglycerides, glycols, polyols and surface-active agents.

Suitably the compound of formula (I) is administered topically to thelung. Hence we provide according to the invention a pharmaceuticalcomposition comprising a compound of the disclosure optionally incombination with one or more topically acceptable diluents or carriers.Topical administration to the lung may be achieved by use of an aerosolformulation. Aerosol formulations typically comprise the activeingredient suspended or dissolved in a suitable aerosol propellant, suchas a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFCpropellants include trichloromonofluoromethane (propellant 11),dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane(propellant 12). Suitable HFC propellants include tetrafluoroethane(HFC-134a) and heptafluoropropane (HFC-227). The propellant typicallycomprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalationcomposition. The formulation may comprise excipients includingco-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitantrioleate and the like). Aerosol formulations are packaged in canistersand a suitable dose is delivered by means of a metering valve (e.g. assupplied by Bespak, Valois or 3M).

Topical administration to the lung may also be achieved by use of anon-pressurised formulation such as an aqueous solution or suspension.This may be administered by means of a nebuliser. Topical administrationto the lung may also be achieved by use of a dry-powder formulation. Adry powder formulation will contain the compound of the disclosure infinely divided form, typically with a mass mean diameter (MMAD) of 1-10microns. The formulation will typically contain a topically acceptablediluent such as lactose, usually of large particle size e.g. a mass meandiameter (MMAD) of 100 μm or more. Example dry powder delivery systemsinclude SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.

Compounds according to the disclosure are intended to have therapeuticactivity. In a further aspect, the present invention provides a compoundof the disclosure for use as a medicament.

Compounds according to the disclosure may also be useful in thetreatment of respiratory disorders including COPD (including chronicbronchitis and emphysema), asthma, paediatric asthma, cystic fibrosis,sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis,sinusitis, especially asthma, chronic bronchitis and COPD.

Compounds of the disclosure may also re-sensitise the patient'scondition to treatment with a corticosteroid, when the patient'scondition has become refractory to the same.

Compounds according to the disclosure are also expected to be useful inthe treatment of certain conditions which may be treated by topical orlocal therapy including allergic conjunctivitis, conjunctivitis,allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis,inflamed joints secondary to rheumatoid arthritis or osteoarthritis.

Compounds of the disclosure are also expected to be useful in thetreatment of certain other conditions including rheumatoid arthritis,pancreatitis, cachexia, inhibition of the growth and metastasis oftumours including non-small cell lung carcinoma, breast carcinoma,gastric carcinoma, colorectal carcinomas and malignant melanoma.

Compounds of the disclosure are believed to be useful as anti-viralagents, for example in the treatment of conditions including influenza.In particular the compounds of the present disclosure may be suitablefor the use in the treatment or prevention of said viral infection andin particular may be capable of reducing viral load and/or amelioratingsymptoms after infection.

Thus, in a further aspect, the present invention provides a compound asdescribed herein for use in the treatment of the above mentionedconditions.

In a further aspect, the present invention provides use of a compound asdescribed herein for the manufacture of a medicament for the treatmentof the above mentioned conditions.

In a further aspect, the present invention provides a method oftreatment of the above mentioned conditions which comprisesadministering to a subject an effective amount of a compound of thedisclosure or a pharmaceutical composition thereof.

The word “treatment” is intended to embrace prophylaxis as well astherapeutic treatment.

A compound of the disclosure may also be administered in combinationwith one or more other active ingredients e.g. active ingredientssuitable for treating the above mentioned conditions. For examplepossible combinations for treatment of respiratory disorders includecombinations with steroids (e.g. budesonide, beclomethasonedipropionate, fluticasone propionate, mometasone furoate, fluticasonefuroate), beta agonists (e.g. terbutaline, salbutamol, salmeterol,formoterol) and/or xanthines (e.g. theophylline).

EXPERIMENTAL SECTION

Abbreviations

Abbreviations used herein are as defined in the table below. Anyabbreviations not defined are intended to convey their generallyaccepted meaning.

-   AcOH glacial acetic acid-   aq aqueous-   Ac acetyl-   ATP adenosine-5′-triphosphate-   BALF bronchoalveolae lavage fluid-   9-BBN 9-borabicyclo[3.3.1]nonane-   Boc tert-butoxycarbonyl-   br broad-   BSA bovine serum albumin-   CatCart® catalytic cartridge-   CBz benzyloxycarbonyl-   CDI 1,1-carbonyl-diimidazole-   COPD chronic obstructive pulmonary disease-   d doublet-   DCM dichloromethane-   DIAD diisopropylazadicarboxylate-   DIBAL-H diisobutylaluminium hydride-   DIPEA N,N-diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EDC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. hydrochloride-   (ES⁺) electrospray ionization, positive mode-   Et ethyl-   EtOAc ethyl acetate-   FCS foetal calf serum-   HOBt 1-hydroxybenzotriazole-   hr hour(s)-   HRP horseradish peroxidase-   JNK c-Jun N-terminal kinase-   KHMDS potassium hexamethyldisilazane-   (M+H)⁺ protonated molecule-   MAPK mitogen protein activated protein kinase-   Me methyl-   MeCN acetonitrile-   MeOH methanol-   MHz megahertz-   min minute(s)-   MOM-Br bromomethyl methyl ether-   MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-   m/z: mass-to-charge ratio-   NMM N-methylmorpholine; (4-methylmorpholine)-   NMP 1-methylpyrrolidin-2-one (N-methyl-2-pyrrolidone)-   NMR nuclear magnetic resonance (spectroscopy)-   Oxone® potassium peroxymonosulfate-   Ph phenyl-   PBS phosphate buffered saline-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (0)-   PPh₃ triphenylphosphine-   PyBOP® (benzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate-   q quartet-   RT room temperature-   RP HPLC reverse phase high performance liquid chromatography-   s singlet-   SCX solid supported cation exchange (resin)-   SDS sodium dodecyl sulphate-   S_(N)Ar nucleophilic aromatic substitution-   t triplet-   TBAF tetrabutylammonium fluoride-   TBDMS-Cl tert-butyldimethylchlorosilane-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMB 3,3′,5,5′-tetramethylbenzidine-   TNFα tumor necrosis factor alpha-   TMS-Cl trimethylsilyl chloride [chlorotrimethylsilane]-   XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene    General Procedures

All starting materials and solvents were either obtained from commercialsources or prepared according to the literature citation. Unlessotherwise stated all reactions were stirred. Organic solutions wereroutinely dried over anhydrous magnesium sulfate. Hydrogenations werepreformed on a Thales H-cube flow reactor under the conditions stated.

Column chromatography was performed on pre-packed silica (230-400 mesh,40-63 μM) cartridges using the amount indicated. SCX was purchased fromSupelco and treated with 1M hydrochloric acid prior to use. Unlessstated otherwise the reaction mixture to be purified was first dilutedwith MeOH and made acidic with a few drops of AcOH. This solution wasloaded directly onto the SCX and washed with MeOH. The desired materialwas then eluted by washing with 1% NH₃ in MeOH.

Preparative Reverse Phase High Performance Liquid Chromatography:

Agilent Scalar column C18, 5 μm (21.2×50 mm), flow rate 28 mL·min⁻¹eluting with a H₂O-MeCN gradient containing 0.1% v/v formic acid over 10min using UV detection at 215 and 254 nm. Gradient information: 0.0-0.5min; 95% H₂O-5% MeCN; 0.5-7.0 min; ramped from 95% H₂O-5% MeCN to 5%H₂O-95% MeCN; 7.0-7.9 min; held at 5% H₂O-95% MeCN; 7.9-8.0 min;returned to 95% H₂O-5% MeCN; 8.0-10.0 min; held at 95% H₂O-5% MeCN.

Analytical Methods

Reverse Phase High Performance Liquid Chromatography:

Method 1: Agilent Scalar column C18, 5 μm (4.6×50 mm) or Waters XBridgeC18, 5 μm (4.6×50 mm) flow rate 2.5 mL·min⁻¹ eluting with a H₂O-MeCNgradient containing either 0.1% v/v formic acid (Method 1 acidic) or NH₃(Method 1 basic) over 7 min employing UV detection at 215 and 254 nm.Gradient information: 0.0-0.1 min, 95% H₂O-5% MeCN; 0.1-5.0 min, rampedfrom 95% H₂O-5% MeCN to 5% H₂O-95% MeCN; 5.0-5.5 min, held at 5% H₂O-95%MeCN; 5.5-5.6 min, held at 5% H₂O-95% MeCN, flow rate increased to 3.5mL·min⁻¹; 5.6-6.6 min, held at 5% H₂O-95% MeCN, flow rate 3.5 mL·min⁻¹;6.6-6.75 min, returned to 95% H₂O-5% MeCN, flow rate 3.5 mL·min⁻¹;6.75-6.9 min, held at 95% H₂O-5% MeCN, flow rate 3.5 mL·min⁻¹; 6.9-7.0min, held at 95% H₂O-5% MeCN, flow rate reduced to 2.5 mL·min⁻¹.

Method 2: Agilent Extend C18 column, 1.8 μm (4.6×30 mm) at 40° C.; flowrate 2.5-4.5 mL·min⁻¹ eluting with a H₂O-MeCN gradient containing 0.1%v/v formic acid over 4 min employing UV detection at 254 nm. Gradientinformation: 0-3.00 min, ramped from 95% H₂O-5% MeCN to 5% H₂O-95% MeCN;3.00-3.01 min, held at 5% H₂O-95% MeCN, flow rate increased to 4.5mL·min⁻¹; 3.01-3.50 min, held at 5% H₂O-95% MeCN; 3.50-3.60 min,returned to 95% H₂O-5% MeCN, flow rate reduced to 3.50 mL·min⁻¹;3.60-3.90 min, held at 95% H₂O-5% MeCN; 3.90-4.00 min, held at 95%H₂O-5% MeCN, flow rate reduced to 2.5 mL·min⁻¹.

¹H NMR Spectroscopy:

Bruker Avance III 400 MHz using residual undeuterated solvent asreference

COMPOUND EXAMPLES1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-morpholinethoxy)naphthalen-1-yl)urea:BIRB 796

A sample of BIRB 796 was prepared according to the published procedure:Cirillo, P. F., Gilmore, T. A., Hickey, E., Regan, J. and Zhang, L. H.Aromatic Heterocyclic Compounds as Antiinflammatory Agents, WO 00/43384(27 Jul. 2000).

Intermediate A 3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-amine

The aminopyrazole Intermediate A1 was prepared by the condensation ofp-tolylhydrazine hydrochloride and 4,4-dimethyl-3-oxopentanenitrileaccording to the published procedure: Cirillo, P. F. et al., WO2000/43384, 27 Jul. 2000.

Intermediate BN-(4-(2-(4-Aminonaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide

To a solution of ethyl2-(2-(tert-butoxycarbonylamino)pyridin-4-yl)acetate (WO 2007089512)(10.0 g, 35.7 mmol) under N₂ in THF (100 mL), at −78° C., was added asolution of DIBAL in THF (1.0M, 71.0 mL, 71.0 mmol) over 1 hr. Thereaction mixture was stirred at −78 to −60° C. for 40 min and was thenwarmed to −15° C. over 1 hr. The solution was re-cooled to −78° C. andwas treated with a further aliquot of DIBAL solution (36.0 mL, 36.0mmol) and was allowed to warm to −40° C. and stirred for 1 hr. Thereaction was quenched by the cautious addition of water (10 mL),followed MgSO₄. The solids were removed by filtration and the filtratewas evaporated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 330 g, EtOAc in hexanes, 65% v/v, isocraticelution) to give tert-buty 4-(2-hydroxyethyl)pyridin-2-ylcarbamate, (6.0g, 64%) as a yellow solid: m/z 239 (M+H)⁺ (ES⁺).

To a solution of tert-butyl 4-(2-hydroxyethyl)pyridin-2-ylcarbamate (6.0g, 25 mmol) in THF (70 mL) at 0° C. was added sodium hydride (2.52 g,60% wt dispersion in mineral oil, 63.0 mmol) and the bright yellowsuspension stirred for 20 min and then treated with1-fluoro-4-nitronaphthalene (4.81 g, 25.2 mmol) in a single portion.After stirring at RT for 2 hr the mixture was treated with water (100mL) followed by EtOAc (100 mL) and the solid which formed at theinterface was collected by filtration. The organic phase was separatedand was washed with saturated aq. NaHCO₃ and brine and was then driedand evaporated in vacuo to furnish an orange solid. The two solids werecombined and triturated with MeOH (50 mL) to provide tert-butyl4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate, as a yellowsolid (11.0 g, 98%): m/z 410 (M+H)⁺ (ES⁺).

To a suspension of tert-butyl4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (900 mg,2.20 mmol) in DCM (10.0 mL) was added TFA (10.0 mL) and the reactionmixture was stirred at RT overnight. The resulting mixture wasevaporated in vacuo and the residue subjected to SCX capture andrelease. The crude product so obtained was taken up into THF (8.0 mL)and DIPEA (660 μl, 3.8 mmol) and then acetyl chloride (147 μl, 2.06mmol) were added. After stirring for 1 hr, the mixture was diluted withsaturated aq. NaHCO₃ (10.0 mL) and was extracted with EtOAc (2×20 mL).The combined organic layers were washed with brine and then dried, andevaporated in vacuo. The residue was taken up in a mixture ofacetonitrile and a solution of NH₃ in MeOH (7M, 1:1 v/v, 20 mL) andafter 10 min was re-evaporated in vacuo. The residue was triturated withMeOH (10.0 mL) to affordN-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide, as ayellow solid (570 mg, 74%): m/z 352 (M+H)⁺ (ES⁺).

A solution ofN-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide (570 mg,1.62 mmol) in a mixture of AcOH: MeOH (6:1 v/v, 54 mL) was subjected tohydrogenation by passage through a Thales H-cube (1 mL·min⁻¹, 30 mm, 10%Pt/C Cat-Cart, full H₂, 45° C.). The solvent was removed by evaporationin vacuo, and, the residue was subjected to SCX capture and release tofurnish the title compound, Intermediate B, (550 mg, 100%): m/z 322(M+H)⁺ (ES⁺).

Intermediate C1-(4-((2-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-M-p-tolyl-1H-pyrazol-5-yl)urea

To a solution of 4-nitronaphthol (5.17 g, 27.3 mmol), triphenylphosphine(10.75 g, 41.0 mmol) and 2-aminopyridine-4-methanol (5.09 g, 41.0 mmol)in THF (50 mL) at −15° C. was added dropwise DIAD (8.07 mL, 41.0 mmol)and the mixture then allowed to warm to RT and stirred overnight. Thevolatiles were removed in vacuo and the residue was triturated withEtOAc (150 mL), and the crude product was collected by filtration andwashed with EtOAc (100 mL). A second trituration with MeOH (100 mL) gave2-amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine (4.54 g, 56%) as ayellow solid: m/z 296 (M+H)⁺ (ES⁺).

A solution of 2-amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine(4.50 g, 15.24 mmol) in MeOH (200 mL) and AcOH (200 mL) was passedthrough a Thales H-cube (2.0 mL·min⁻¹, 40° C., 55 mm 10% Pt/C Cat-Cart,full hydrogen mode) and the volatiles were removed in vacuo. The crudeproduct was subjected to SCX capture and release and the solvent wasremoved in vacuo to give2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine, (3.82 g, 94%) asa purple solid: m/z 266 (M+H)⁺ (ES⁺).

A solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL) was added dropwiseunder nitrogen to a solution of Intermediate A (5.91 g, 25.8 mmol) inDCM (15 mL) over 40 min. The resulting solution was stirred at RT for 1hr and was then added dropwise under nitrogen to a solution of2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine (3.80 g, 12.9mmol) in DCM and the mixture was stirred overnight. The volatiles wereremoved in vacuo. and the residue was purified by flash columnchromatography (SiO₂, 120 g, MeOH in DCM, 0-6%, gradient elution) togive the tite compound, Intermediate C, as an off white solid (4.27 g,63%): m/z 521 (M+H)⁺ (ES⁺).

Intermediate D1-(4-(2-Aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-toly-1H-pyrazol-5-yl)urea

To a stirred solution of 2-chloro-4-fluoropyridine (1.26 g, 9.58 mmol)and 4-amino-1-naphthol hydrochloride (750 mg, 3.83 mmol) in NMP (40 mL)at −20° C. was added potassium tert-butoxide (1.29 g, 11.50 mmol) andthe reaction mixture then warmed to RT for 2.5 hr. The mixture wasdiluted with water (100 mL) and extracted with EtOAc (100 mL and 2×80mL) and the combined organic extracts were washed with brine (150 mL),dried and evaporated in vacuo. The crude product was subjected to SCXcapture and release and the volatiles were removed in vacuo to give4-(2-chloropyridin-4-yloxy)naphthalen-1-amine as a brown solid (1.02 g,92%): m/z 271 (M+H)⁺ (ES⁺).

To a stirred solution of 4-(2-chloropyridin-4-yloxy)naphthalen-1-amine(1.02 g, 3.76 mmol) in THF (30 mL) at 0° C. was added DMAP (34 mg, 0.282mmol) and then di-tert-butyl dicarbonate (904 mg, 4.14 mmol). Thereaction mixture was stirred at 0° C. for 30 min and was then allowed towarm to RT. After 1.5 hr the mixture was re-cooled to 0° C. and anadditional aliquot of di-tert-butyl dicarbonate (904 mg, 4.14 mmol) wasadded. The resulting mixture was stirred at 0° C. for 15 min and at RTfor 16 hr and was diluted with water (40 mL) and extracted with EtOAc(2×40 mL). The combined organic extracts were washed with brine (75 mL),dried and evaporated in vacuo. The residue was purified by flash columnchromatography (SiO₂, 80 g, 0-40% EtOAc in iso-hexane, gradient elution)to give4-(2-chloropyridin-4-yloxy)naphthalen-1-N,N-di-tert-butylcarbarmate as apurple solid (892 mg, 48%): m/z 471 (M+H)⁺ (ES⁺).

A mixture of4-(2-chloropyridin-4-yloxy)naphthalen-1-N,N-di-tert-butylcarbamate (892mg, 1.89 mmol), tert-butyl carbamate (666 mg, 5.68 mmol), caesiumcarbonate (926 mg, 2.84 mmol), Pd₂(dba)₃ (43 mg, 0.047 mmol) andXantPhos (55 mg, 0.095 mmol) was suspended in THF (10.0 mL) and waspurged thoroughly with nitrogen and then heated to reflux for 15 hr. Themixture was cooled to RT and diluted with water (35 mL) and wasextracted with EtOAc (35 mL and 25 mL). The combined organic extractswere washed with brine (50 mL), dried and evaporated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, 80 g, 0-30%EtOAc in iso-hexane, gradient elution) to give tert-butyl4-(4-(N,N-di-(tert-butyloxycarbonyl)amino)naphthalen-1-yloxy)pyridin-2-yl carbamate, as a whitesolid (289 mg, 28%): m/z 552 (M+H)⁺ (ES⁺).

To a stirred solution of tert-butyl4-(4-(N,N-di-(tert-butyloxycarbonyl)amino)naphthalen-1-yloxy)pyridin-2-ylcarbamate (289 mg, 0.524 mmol) in DCM (8.0 mL), at 0° C., was added TFA(4.0 mL) and the resulting mixture allowed to warm to RT. After 5 hr thevolatiles were removed in vacuo and the residue was taken up in MeOH(5.0 mL) and subjected to SCX capture. The volatiles were removed invacuo to provide 4-(4-aminonaphthalen-1-yloxy)pyridin-2-amine, (116 mg,85%) as a brown-orange oil: m/z 252 (M+H)⁺ (ES⁺).

To a vigorously stirred mixture of Intermediate A (206 mg, 0.900 mmol)in DCM (20 mL) and saturated aq. NaHCO₃ (14 mL) at 0° C. was addedtrichloromethylchloroformate (325 μL, 2.70 mmol) in a single portion andthe stirring continued at 0° C. for 80 min. The organic layer wasseparated and dried and was evaporated in vacuo to provide3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole, as an orange oil. Thismaterial was pumped under high vacuum for 30 min and was then taken upinto THF (6.0 mL) and the resulting solution kept under nitrogen at 0°C. for use in the next step.

To a stirred solution of 4-(4-aminonaphthalen-1-yloxy)pyridin-2-amine,(116 mg, 0.462 mmol) and DIPEA (240 μl, 1.39 mmol) in THF (3.0 mL) at 0°C. was added an aliquot of the isocyanate solution prepared above (2.0mL, 0.300 mmol) and the resulting mixture allowed to warm to RT.Additional aliquots of the isocyanate solution were added to thereaction mixture after 1.5 hr, (1.0 mL, 0.150 mmol) and after a further3.5 hr (0.5 mL, 0.075 mmol). The mixture was maintained at RT for 20 hrand was then diluted with water (30 mL) and was extracted with EtOAc(2×30 mL). The combined organic extracts were washed with brine (50 mL),dried and then evaporated in vacuo. The residue was purified by flashcolumn chromatography (SiO₂; 12 g, 25-100% [5% MeOH in EtOAc] iniso-hexane, gradient elution) to furnish the title compound IntermediateD, as a brown oil (127 mg, 49%): m/z 507 (M+H)⁺ (ES⁺).

Example 1N-(4-(2-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide

To a suspension of CDI (416 mg, 2.57 mmol) in DCM (1.0 mL) was added asolution of Intermediate A (589 mg, 2.57 mmol) in DCM (2.0 mL) over 1.5hr and after 1 hr a solution of Intermediate B (550 mg, 1.711 mmol) inDCM (6.0 mL) was added and the reaction mixture maintained at RT for 16hr. The reaction mixture was loaded directly on to silica and waspurified by flash column chromatography (SiO₂, 40 g, EtOAc in isohexane,50-100%, gradient elution) to afford the title compound, Example 1, (700mg, 71%): m/z 577 (M+H)⁺ (ES⁺). ¹H NMR (400 MHz, DMSO-dr) δ: 1.26 (9 H,s), 2.08 (3 H, s), 2.38 (3 H, s), 3.20 (2H, t), 4.37 (2H, t), 6.34 (1H,s), 6.95 (1H, d), 7.15 (1H, dd), 7.35 (2H, m), 7.45 (3H, overlapping m),7.55 (1H, m), 7.60 (1H, m), 7.90 (1H, d), 8.20 (3H, overlapping m), 8.57(1H, s), 8.77 (1H, s) and 10.40 (1H, s).

Example 2N-(4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)methyl)pyridin-2-yl)acetamide

To a mixture of Intermediate C (40 mg, 0.08 mmol) and DIPEA (15 μL, 0.09mmol) in DCM/DMF (10:1, 1.1 mL) was added acetyl chloride (6 μL, 0.08mmol). After stirring for 40 min RT, further DIPEA (15 μL, 0.09 mmol)and acetyl chloride (6 μL, 0.08 mmol) were added sequentially andstirring was continued for 30 min. The reaction mixture was diluted withAcOH and subjected to purification by SCX capture and release. The crudeproduct so obtained was triturated with DCM to afford the titlecompound, Example 2, as a pale orange solid (21 mg, 50%); R¹ 3.86 min(Method 1 basic); m/z 563 (M+H)⁺ (ES⁺). ¹H NMR (400 MHz, DMSO-d₆) δ:1.29 (9 H, s), 2.10 (3H, s), 2.39 (3 H, s), 5.36 (2H, s), 6.35 (1H, s),7.01 (1H, d), 7.23 (1H, dd), 7.36 (2H, d), 7.44 (2H, d), 7.57-7.63 (3H,overlapping m), 7.92 (1H, m), 8.29-8.33 (3H, overlapping m), 8.59 (1H,s), 8.79 (1H, s), 10.53 (1H, s).

Example 3 N-(4-((4-(3-(3-(tert-Butyl)-1(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)acetamide

To a mixture of1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea(40 mg, 0.08 mmol) and DIPEA (69 μL, 0.40 mmol) in THF (5.0 mL) at 0° C.under N₂ was added acetyl chloride (22 μL, 0.08 mmol) and the mixturemaintained at 0° C. for 30 min and then warmed to RT for 16 hr. Thereaction was quenched by the addition of a solution of NH₃ in MeOH (1%w/v, 2.0 mL) and after 45 min at RT the volatiles were evaporated invacuo. The residue was subjected to purification by SCX capture andrelease and then by flash column chromatography (SiO₂, 12 g, [5% MeOH inEtOAc] in isohexane, 0-70%, gradient elution). The impure material soobtained was subjected to re-purification by SCX capture and release andby flash column chromatography (SiO₂, 12 g, [5% MeOH in EtOAc] inisohexane, 0-65%, gradient elution) to afford the title compound,Example 3, as a white solid (12 mg, 27%); R¹ 2.26 min (Method 2); m/z549 (M+H)⁺ (ES⁺). ¹H NMR (400 MHz, DMSO-d₆) δ: 1.29 (9 H, s), 2.01 (3H,s), 2.38 (3 H, s), 6.39 (1H, s), 6.63 (1H, dd), 7.31 (1H, d), 7.36 (2H,d), 7.48 (2H, d), 7.56 (1H, m), 7.61-7.66 (2H, overlapping m), 7.83 (1H,d), 7.96 (1H, d), 8.16 (1H, d), 8.19 (1H, d), 9.02 (1H, s), 9.30 (1H,s), 10.52 (1H, s).

Biological Testing: Experimental Methods

Enzyme Inhibition Assay

The enzyme inhibitory activities of compounds disclosed herein weredetermined by fluorescence resonance energy transfer (FRET) usingsynthetic peptides labelled with both donor and acceptor fluorophores(Z-LYTE, Invitrogen Ltd., Paisley, UK). Recombinant, phosphorylated p38MAPKγ (MAPK12:Invitrogen) was diluted in HEPES buffer, mixed with thetest compound at the desired final concentrations and incubated for 2 hrat RT. The FRET peptide (2 μM) and ATP (100 μM) were added to theenzyme/compound mixture and incubated for 1 hr. Development reagent(protease) was added for 1 hr prior to detection in a fluorescencemicroplate reader (Varioskan® Flash, ThermoFisher Scientific). Thesite-specific protease cleaves non-phosphorylated peptide only andeliminates the FRET signal. Phosphorylation levels of each reaction werecalculated using the ratio of coumarin emission (donor) over fluoresceinemission (acceptor) for which high ratios indicate high phosphorylationand low ratios indicate low phosphorylation levels. The percentageinhibition of each reaction was calculated relative to non-inhibitedcontrol and the 50% inhibitory concentration (IC₅₀ value) thencalculated from the concentration-response curve.

For the p38 MAPKα isoform (MAPK14: Invitrogen), enzyme activity wasevaluated indirectly by determining the level ofactivation/phosphorylation of the down-stream molecule, MAPKAP-K2. Thep38 MAPKα protein was mixed with the test compound for 2 hr at RT. Thep38α inactive target MAPKAP-K2 (Invitrogen) and FRET peptide (2 μM),which is a phosphorylation target for MAPKAP-K2, and ATP (10 μM) werethen added to the enzymes/compound mixture and the resulting mixtureincubated for 1 hr. Development reagent was then added and the mixtureincubated for 1 hr before detection by fluorescence completed the assayprotocol.

Cellular Potency Assays:

1) LPS-Induced TNFα/IL-8 Release in d-U937Cells

U937 cells, a human monocytic cell line, were differentiated tomacrophage-type cells by incubation with phorbol myristate acetate (PMA;100 ng/ml) for 48 to 72 hr. Cells were pre-incubated with finalconcentrations of test compound for 2 hr and were then stimulated with0.1 μg/mL of LPS (from E. Coli: O111:B4, Sigma) for 4 hr. Thesupernatant was collected for determination of TNFα and IL-8concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibitionof TNFα production was calculated as a percentage of that achieved by 10μg/mL of BIRB796 at each concentration of test compound by comparisonagainst vehicle control. The relative 50% effective concentration(REC₅₀) was determined from the resultant concentration-response curve.The inhibition of IL-8 production was calculated at each concentrationof test compound by comparison with vehicle control. The 50% inhibitoryconcentration (IC₅₀) was determined from the resultantconcentration-response curve.

2) LPS-Induced TNFα Release in THP-1 Cells

THP-1 cells, a human monocytic cell line, were stimulated with 3 μg/mLof LPS (from E. Coli: 0111:B4, Sigma) for 4 hr and the supernatantcollected for determination of the TNFα concentration by sandwich ELISA(Duo-set, R&D systems). The inhibition of TNFα production was calculatedat each concentration by comparison with vehicle control. The 50%inhibitory concentration (IC₅₀) was determined from the resultantconcentration-response curve.

3) Poly I:C-Induced ICAM-1 Induction in BEAS2B Cells

Poly I:C (1 μg/m) (Invivogene Ltd., San Diego, Calif.) was transfectedinto BEAS2B cells (human bronchial epithelial cells, ATCC) withOligofectamine (Invitrogen, Carlsbad, Calif.). Cells were pre-incubatedwith final concentrations of test compounds for 2 hr and the level ofICAM1 expression on the cell surface was determined by cell-based ELISA.At a time point 18 hr after poly I:C transfection, cells were fixed with4% formaldehyde in PBS. and then endogenous peroxidase was quenched bythe addition of 0.1% sodium azide and 1% hydrogen peroxide. Cells werewashed with wash-buffer (0.1% Tween in PBS: PBS-Tween). and afterblocking the wells with 5% milk in PBS-Tween for 1 hr, the cells wereincubated with anti-human ICAM-1 antibody (Cell Signaling Technology,Danvers, Mass.) in 1% BSA PBS overnight at 4° C. The cells were washedwith PBS-Tween and incubated with the secondary antibody (HRP-conjugatedanti-rabbit IgG, Dako Ltd., Glostrup, Denmark). The ICAM-1 signal wasdetected by adding substrate and reading the absorbance at 450 nmagainst a reference wavelength of 655 nm using a spectrophotometer. Thecells were then washed with PBS-Tween and total cell numbers in eachwell were determined by reading absorbance at 595 nm after CrystalViolet staining and elution by 1% SDS solution. The measured OD 450-655readings were corrected for cell number by dividing with the OD595reading in each well. The inhibition of ICAM-1 expression was calculatedat each concentration of test compound by comparison with vehiclecontrol. The 50% inhibitory concentration (IC₅₀) was determined from theresultant concentration-response curve.

MTT Assay: Cell Viability

Differentiated U937 cells were pre-incubated with each test compoundunder two protocols: the first for 4 hr in 5% FCS and the second in 10%FCS for 24 h. The supernatant was replaced with 200 μL of new media and10 μL of MTT stock solution (5 mg/mL) was added to each well. Afterincubation for 1 hr the media were removed, 200 μL of DMSO was added toeach well and the plates were shaken lightly for 1 hr prior to readingthe absorbance at 550 nm. The percentage loss of cell viability wascalculated for each well relative to vehicle (0.5% DMSO) treatment.Consequently an apparent increase in cell viability for drug treatmentrelative to vehicle is tabulated as a negative percentage.

The in vitro profiles of the compound examples disclosed herein, asdetermined using the protocols described above, are presented below(Table 1).

TABLE 1 In Vitro Profiles of Compound Examples Cellular ProfilesLPS/TNFα LPS-IL8 Enzyme Inhibition THP-1 d-U937 Example IC₅₀ (nM) IC₅₀REC₅₀ IC₅₀ MTT Assay ^(a) No p38α p38γ HCK c-Src (nM) (nM) (nM) 4 h 24 hBIRB796 12 296  NE^(b) NE^(b) 4.1 4.8  NE^(b) − − 2 2.5 195 NT 166 NT3.6 NT −  +^($) 3 6.7 146 NT <18 1.6 1.0 NT − + ^(a) Cell ViabilityAssay: + = >30% inhibition; − = <30% inhibition at 10 μg/ml; ^($)=negative at 1 μg/ml; ^(b)No effect at a concentration of 1 ug/ml

The invention claimed is:
 1. A compound of formula (I):

wherein: J represents

Ar is a naphthylene; Q is CH; R¹ is a saturated branched or unbranched C₁₋₁₀ alkylene chain; R^(2a) is saturated branched or unbranched C₁₋₈ alkylene chain; R^(2b) is H; L is selected from the group consisting of —O, —OCH₂—, —OCH₂CH₂—, S and SO₂; X is a pyridine ring; R³ is H; R⁴ is C₁₋₁₀ branched or unbranched, unsubstituted alkyl chain; or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
 2. A compound of formula (I) according to claim 1, wherein R¹ is methyl, ethyl, propyl, iso-propyl, butyl or tert-butyl.
 3. A compound of formula (I) according to claim 1, wherein R¹ is tert-butyl.
 4. A compound of formula (I) according to claim 1, wherein R^(2a) is in the ortho, meta or para position.
 5. A compound of formula (I) according to claim 1, wherein R^(2a) is methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, in particular methyl.
 6. A compound of formula (I) according to claim 1, wherein R^(2a) is methyl.
 7. A compound of formula (I) according to claim 1, wherein L is O.
 8. A compound of formula (I) according to claim 1, wherein L represents —OCH₂— or —OCH₂CH₂—.
 9. A pharmaceutical composition comprising a compound according to claim 1, in combination with one or more pharmaceutically acceptable diluents or carriers.
 10. The compound according to claim 1, wherein the compound is selected from the group consisting of N-(4-(2-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)4yridine4ne-1-yloxy)ethyl)4yridine-2-yl)acetamide; N-(4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)4yridine4ne-1-yl) oxy)methyl)4yridine-2-yl)acetamide; and N-(4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)4yridine4ne-1-yl) oxy)4yridine-2-yl)acetamide.
 11. The compound according to claim 1, wherein R^(2a) is methyl; L is O; and R⁴ is methyl.
 12. The compound according to claim 1, wherein R^(2a) is methyl; L is —OCH₂—; and R⁴ is methyl.
 13. The compound according to claim 1, wherein R^(2a) is methyl; L is —OCH₂CH₂—; and R⁴ is methyl. 